The chemotherapeutic drug cisplatin (cis-diamminedichloroplatinum or CDDP) was discovered to have cytotoxic properties in 1968 and is used extensively worldwide in the treatment of many tumors, in particular solid tumors such as ovarian cancer, testicular cancer and head and neck cancers. This platinum drug is thought to act by platination of DNA, thereby crosslinking DNA (both interstrand and intrastrand) and disrupting cellular processes. The clinical effectiveness of cisplatin is limited by the occurrence of cisplatin-resistant cancer cells. Certain tumors exhibit intrinsic or natural resistance to cisplatin and undergo no regression even upon initial chemotherapeutic treatment. Other tumors respond well to initial treatment but upon relapse exhibit reduced responsiveness to the drug. This type of resistance, which occurs after a course of therapy with cisplatin, is termed acquired resistance. The ability to prevent, overcome or reverse cisplatin resistance would be of great benefit to the treatment of malignant diseases.
Attempts have been made to identify the mechanism of cisplatin resistance but this mechanism remains to be elucidated. In various studies, cisplatin resistance has been associated with reduced intracellular accumulation of the drug, increased DNA repair function and/or increased drug detoxification by intracellular thiols (for reviews of possible mechanism of cisplatin resistance see e.g. Andrews, P. A. and Howell, S. B. (1990) Cancer Cells 2:35-43; Kelley, S. L. and Rozencweig, M. (1989) Eur. J. Clin. Oncol 25:1135-1140; Perez, R. P. et al. (1990) Pharmacol. Ther. 48:19-27; and Timmer-Bosscha, H. et al. (1992) Br. J. Cancer 66:227-238). A role for drug detoxification by intracellular thiols has been postulated due to an association of cisplatin resistance in certain cancer cell lines with increased levels of glutathione and metallothionein (see e.g. Godwin, A.K. et al. (1992) Proc. Natl. Acad Sci. USA 89:3070-3074; and Kelley, S. L. et al. (1988) Science 241:1813-1815).
Attempts have also been made to implicate particular genes with acquisition of a cisplatin resistant phenotype. For example, glutathione transferase (GST) and metallothionein genes have been transfected into cell lines to try to confer cisplatin resistance on the cells. GST has been reported to confer cisplatin resistance on cells but the level of increased resistance was only in the range of 1.5 to 3.0 fold (see e.g. Miyazaki, M. et al. (1990) Biochem. Biophys. Res. Commun. 166:1358-1364; and Puchalski, R. B. et al. (1990) Proc. Natl. Acad Sci. USA 87:2443-2447). Another study has reported that transfection of cells with a metallothionein gene can confer cisplatin resistance on cells but again the level of increased resistance was less than 5-fold (see Kelley, S. L. et al. (1988) Science 241:1813-1815) and other studies found no increase in cisplatin resistance upon transfection of cells with the metallothionein gene (see Morton, K. A. et al. (1993) J. Pharmacol Exp. Ther. 267:697-702; and Koropatnick, J. and Pearson, J. (1993) Molec. Pharmacol 44:44-50). In another study, cells transfected with the c-myc gene were reported to have acquired resistance to cisplatin but once again the level of increased resistance was very low (i.e., less than 3- fold).
Multidrug resistance of tumor cells to anthracyclines (e.g. doxorubicin, epipodophyllotoxins and Vinca alkaloids) has been found to be associated with increased expression of one of two different genes, one encoding P-glycoprotein (see Roninson, I. B. et al. (1984) Nature 309:626-628; and Riordan, J. R. et al. (1985) Nature 316:817-819) and the other encoding MRP (see Cole, S. P. C. et al. (1992) Science 258:1650-1654). Transfection of cells with the mdrl gene (encoding P-glycoprotein) or with the MRP gene can confer multidrug resistance en the cells (see Gros, P. et al. (1986) Nature 323:728-731; and Cole, S. P. C. (1994) Cancer Res. 54:357-361). However, neither P-glycoprotein or MRP are able to confer on a cell high level resistance to cisplatin and therefore do not account for cisplatin resistance observed in tumor cells.
None of studies described above convincingly account for the observed intrinsic or acquired cisplatin resistance of tumor cells. Thus, it can be concluded that a cisplatin resistance-determining gene, which can confer high levels of cisplatin resistance on a cell, remains to be identified.